Sweet sensors support stressed cell survival

Gustatory receptors (Grs) are well known for their functions in sensory neurons in detecting food and toxins. An intriguing new study in PLOS Biology provides evidence for a role for Grs in Drosophila epithelia in protecting stressed cells from proteotoxicity.

To understand how Gr64 genes contribute to cell survival under stressed conditions, the authors restricted Gr64 RNAi to the posterior compartment of the wing disc (in an RpS3 +/− background) that led to a milder phenotype, with low frequency of cell death, and compared the expression of various markers of cell stress in anterior (control) and posterior compartments. Knock-down of Gr64s led to modest increases in expression of a reporter for the oxidative stress response pathway (GstD1-GFP) and markers for the integrated stress response (phospho-JNK and phospho-eIF2α), consistent with the hypothesis that Gr64s function to attenuate cell stress.
In their previous work [8], the authors showed that stress in RpS3 +/− cells results from accumulation of protein aggregates, due to decreased protein degradation/removal through the proteasome and/or autophagy. In the new study, they probe the mechanistic basis of how Gr64s help promote cell survival using transgenic reporters for the activity of these pathways (Proteoflux for the proteasome and ReFlux for autophagy [8]). Loss of Gr64s reduced both proteasome and autophagosome function, consistent with a model in which these proteins help prevent proteotoxic stress.
This report provides evidence for a new role for Grs in a cell survival pathway ( Fig 1C). As with all provocative discoveries, the work raises several important questions. First, how are Gr64 genes transcriptionally up-regulated in response to cellular stress? The mechanism is likely to be distinct from the developmental pathways controlling the neuron-specific expression of Grs in chemosensory organs ( Fig 1B) [6]. However, Grs (and other chemosensory genes) display plasticity in expression levels in adults, suggesting that other global mechanisms of gene regulation exist. Stress-induced Gr64 expression in wing discs was inferred from bulk RNA-sequencing, so it is unclear whether Gr64 up-regulation depends upon an external signal acting across the tissue or occurs in a cell-autonomous manner. In situ analysis of Gr64 expression is clearly warranted. ; the mechanistic function of Gr64 genes in this process is unclear, but is thought to be largely cell autonomous [5]. https://doi.org/10.1371/journal.pbio.3001705.g001 Second, are Gr64s functioning as ligand-gated channels in stressed cells? While it is reasonable to presume that they have a similar biochemical function to their role in chemosensory neurons, protein localization analyses will be essential to determine if Gr64s are present on the plasma membrane of epithelial cells (and therefore able to respond to extracellular cues) or restricted to intracellular membranes. In either scenario, known Gr64 ligands (sugars, glycerol, and fatty acids [6]) are likely to be available to gate these channels, although whether such chemicals could act as deterministic signals is unclear. Alternatively, Gr64s may function in a ligand-independent manner, conducting ions through spontaneous channel opening. It is notable that other (chemosensory) ionotropic receptors are up-regulated in stressed wing discs [7], raising the possibility that multiple ion channels participate in the proteostasis pathway.
Third, assuming Gr64s do function as channels, how might ion conduction suppress proteotoxic stress? The authors hint that Ca 2+ is involved, through their observation of decreases in frequency of "calcium flashes" in disc cells when Gr64s are down-regulated. However, how Gr64s contribute to such flashes and how this phenomenon is related to regulation of the proteasome or autophagy are completely unknown. Of course, we cannot rule out that the Gr64s have a distinct function in this cellular context, unrelated to their signaling mechanism in sensory neurons.
Despite the abundance of questions, this intriguing work outlines another example of a non-chemosensory function of chemosensory receptors. This role is surprising in the context of our prior appreciation of Gr64s only as sweet sensors, but the Gr superfamily is evolutionarily ancient: Homologs are present in animals, plants, and unicellular eukaryotes, with some, albeit very sparse, evidence for non-chemosensory activities [10]. Further investigation of Gr64s' contribution to protection of cells from stress could illuminate an ancestral function for this protein family.